Profound and controllable anticoagulation is essential during a large number of clinical procedures including percutaneous and surgical revascularization procedures (PCI and CABG), aortic surgery and other vascular interventions. Immediate anticoagulation therapy is also required in a variety of thrombotic diseases such as acute coronary syndromes, pulmonary embolism or deep vein thrombosis. Significant risks and side effects of all of these interventions and therapies include profound bleeding or thrombosis leading to cerebrovascular or cardiovascular compromise. The clinical and financial implications of these outcomes can be profound and are associated with prolonged hospitalization, reduced quality of life, and increased health-care resource utilization. The proposed work extends the basic discoveries of novel therapeutic anticoagulant aptamer/antidote pairs. We believe that a crucial next step in the translation of these agents to clinical practice is the testing in predictive in vitro and animal models such as those we will employ in this project. The proposed work will reveal whether this innovative therapeutic strategy can provide superior anticoagulation in prothrombotic environments, while avoiding undesired effects such as bleeding, platelet dysfunction, systemic inflammation and impaired wound healing.